A T cell resilience model associated with response to immunotherapy in multiple tumor types View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2022-05-02

AUTHORS

Yu Zhang, Trang Vu, Douglas C. Palmer, Rigel J. Kishton, Lanqi Gong, Jiao Huang, Thanh Nguyen, Zuojia Chen, Cari Smith, Ferenc Livák, Rohit Paul, Chi-Ping Day, Chuan Wu, Glenn Merlino, Kenneth Aldape, Xin-yuan Guan, Peng Jiang

ABSTRACT

Despite breakthroughs in cancer immunotherapy, most tumor-reactive T cells cannot persist in solid tumors due to an immunosuppressive environment. We developed Tres (tumor-resilient T cell, https://resilience.ccr.cancer.gov/), a computational model utilizing single-cell transcriptomic data to identify signatures of T cells that are resilient to immunosuppressive signals, such as transforming growth factor-β1, tumor necrosis factor-related apoptosis-inducing ligand and prostaglandin E2. Tres reliably predicts clinical responses to immunotherapy in melanoma, lung cancer, triple-negative breast cancer and B cell malignancies using bulk T cell transcriptomic data from pre-treatment tumors from patients who received immune-checkpoint inhibitors (n = 38), infusion products for chimeric antigen receptor T cell therapies (n = 34) and pre-manufacture samples for chimeric antigen receptor T cell or tumor-infiltrating lymphocyte therapies (n = 84). Further, Tres identified FIBP, whose functions are largely unknown, as the top negative marker of tumor-resilient T cells across many solid tumor types. FIBP knockouts in murine and human donor CD8+ T cells significantly enhanced T cell-mediated cancer killing in in vitro co-cultures. Further, Fibp knockout in murine T cells potentiated the in vivo efficacy of adoptive cell transfer in the B16 tumor model. Fibp knockout T cells exhibit reduced cholesterol metabolism, which inhibits effector T cell function. These results demonstrate the utility of Tres in identifying biomarkers of T cell effectiveness and potential therapeutic targets for immunotherapies in solid tumors. More... »

PAGES

1421-1431

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  • Journal

    TITLE

    Nature Medicine

    ISSUE

    7

    VOLUME

    28

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41591-022-01799-y

    DOI

    http://dx.doi.org/10.1038/s41591-022-01799-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1147542503

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/35501486


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